Expanding Ligand Space: Preparation, Characterization and Syn- thetic Applications of Air-Stable, Odorless Di-tert-alkylphosphine Surrogates Thomas Barber,†,‡ Stephen P. Argent,† and Liam T. Ball†,‡,* † School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K. ‡ GSK Carbon Neutral Laboratories for Sustainable Chemistry, University of Nottingham, Jubilee Campus, Triumph Road, Nottingham, NG7 2TU, U.K. ABSTRACT: The di-tert-alkylphosphino motif is common to many best-in-class ligands for late transition metal catalysis. How- ever, the structural diversity of these privileged substructures is currently limited by the need to manipulate highly toxic, highly reactive reagents and intermediates in their synthesis. In response to this longstanding challenge, we report an umpolung strategy for the synthesis of structurally diverse di-tert-alkylphosphine building blocks via SN1 alkylation of in situ generated PH3 gas. We show that the products – which are isolated as air-stable, odorless phosphonium salts – can be used directly in the preparation of key synthetic intermediates and ligand classes. The di-tert-alkylphosphino building blocks that are accessible using our methodolo- gy therefore enable facile expansion of extant ligand classes by modification of a previously invariant vector; we demonstrate that these modifications impact the steric and electronic properties of the ligands, and can be used to tune their performance in catalysis. Keywords: phosphorus, phosphines, ligand synthesis, cataly- Scheme 1. Occurrence, Conventional Synthesis and Pro- sis, cross-coupling. posed Synthesis of tert-Alkylphosphines Introduction Advances in homogeneous transition metal catalysis have been underpinned by the rational design of sophisticated, ap- plication-specific phosphine ligands. Sterically demanding, electron-rich phosphines bearing tert-alkyl substituents have emerged as especially privileged in polymerization,1 strong- bond activation2 and cross-coupling3 chemistries. While tri- tert-alkylphosphines have huge historical4 and contemporary5 significance, structural modification of this ligand class is extremely challenging.6 In contrast, phosphines featuring two tert-alkyl substituents share many of the desirable attributes of their homoleptic counterparts, but can be conveniently tuned to meet reaction-specific demands through variation of the third, unique substituent.7 As a consequence of this versatility, the di-tert-alkylphosphino (DTAP) motif forms the basis of many current best-in-class ligands (Scheme 1A).7,8,9 Despite the importance of DTAP motifs, the diversity in their tert-alkyl substituents is extremely limited. Indeed, all commercial phosphines featuring this substructure are based on either tert-butyl or 1-adamantyl (Ad) substituents,10 with We anticipated that an umpolung strategy (“P˗/C+”, Scheme just a handful of other examples documented in the patent and 1C) would provide unrivalled access to structurally diverse primary literature.11 Further exploration of this privileged re- DTAP building blocks, and would eliminate the need for gion of ligand space is currently hampered by the practical wasteful redox adjustments at phosphorus. S 1 alkylation challenges associated with the synthesis of new DTAP build- N would enable facile installation of sterically demanding sub- ing blocks. As a case in point, the conventional “P+/C˗” ap- stituents and would open up a much wider pool of alkylating proach to di-tert-alkylphosphines (Scheme 1B)12 involves agents than is available to the conventional P+/C- approach. In manipulation of highly hazardous, air-sensitive reagents and situ generation of both the P-nucleophile and the C- intermediates over multiple steps, is redox-inefficient and is electrophile would ultimately minimize the need to handle ultimately limited in scope by the diversity of the tert- reactive reagents and intermediates. alkylmetal reagents that are available. Herein we report realization of this umpolung approach to neither of which allow installation of tert-alkyl substituents.19 secondary phosphine synthesis. By exploiting an SN1 mani- A single example of SN1-type alkylation was recently reported fold, we demonstrate that di-tert-alkylphosphines can be pre- by Carrow, although a secondary phosphine nucleophile – pared selectively from readily available, bench stable precur- rather than PH3 – was employed in order to generate the 20 sors. The products are obtained as air-stable, odorless phos- homoleptic tertiary phosphine, PAd3. As illustrated in entries phonium salts which can be isolated conveniently by filtration. 1-4, we found that combination of tert-amyl alcohol or tert- The DTAP building blocks that are accessible in this way ena- amyl methyl ether with either HOTf or TMSOTf failed to af- ble facile expansion of extant ligand classes by modification ford appreciable amounts of alkylphosphine products. While of a previously invariant vector; we show that these modifica- the combination of tert-amyl acetate and HOTf proved simi- tions impact the steric and electronic properties of the new larly unsuccessful (entry 5), use of tert-amyl acetate and ligands, and can be used to tune their performance in catalysis. TMSOTf resulted in high-yielding alkylation of PH3 (entry 21 6). Notably, >95% of the phosphonium salt formed in this way was recovered conveniently via precipitation and filtra- Results and Discussion tion under air. The isolated material proved to be a free- Our proposed SN1 strategy (Scheme 1C) requires a synthon flowing, non-hygroscopic and odorless solid that is soluble in 2- of the type “HP ”. While phosphine gas (PH3) is an atom- organic media,22 and that can be stored on the bench for at economic and readily available synthetic equivalent to this least a year without noticeable degradation. Although the yield synthon, we were cognizant of the risks and practical chal- of 1a suffered slightly when a lower stoichiometry of tert- lenges associated with handling high-pressure, cylinderized amyl acetate was employed (entry 7), these more economic 13 PH3. We therefore sought to generate the gas on demand and conditions proved generally applicable in subsequent studies in precise stoichiometries by protonolysis of a metal phos- (vide infra). phide. Specifically, we identified zinc phosphide (Zn P ) as a 3 2 The conditions outlined in entries 6 and 7 of Scheme 2C convenient source of PH because, unlike other metal phos- 3 confer excellent selectivity for dialkylation, with neither phides, it is both bench stable and cheap (£48 /kg).14 While mono- nor trialkylation products observed by 31P NMR spec- Zn P can be stored and handled under an ambient atmosphere, 3 2 troscopy. This remarkable selectivity can be explained by con- it is readily protonolyzed to PH under acidic conditions. We 3 sidering the different basicities of primary, secondary and anticipated that this reactivity could be exploited in the two tertiary phosphines.23 The first-formed primary phosphine is, chamber ‘CO-ware’ reactor system developed by Skrydstrup,15 presumably, insufficiently basic to be fully protonated by the with PH generated in the first chamber from Zn P and con- 3 3 2 HOTf co-product. A second alkylation may therefore occur, sumed in the second chamber by S 1 alkylation (Scheme 2A). N affording a more-basic secondary phosphine which is fully To explore the viability of this strategy, we first confirmed protonated under the reaction conditions. This innate alkyla- that generation of PH3 from Zn3P2 is indeed facile. As deter- tion-dependent change in protonation state constitutes an ef- mined by volumetric gas titration (Scheme 2B), complete hy- fective self-regulation mechanism that prevents over- drolysis of Zn3P2 occurs within 10 minutes of adding excess alkylation, and ensures that the product is obtained as a stable, aqueous HCl. Under these conditions, gas evolution exhibits crystalline phosphonium salt rather than an air-sensitive phos- pseudo first order kinetics with an effective half-life of 110 s phine.24 (Scheme 2B, inset), providing sufficient time for addition of The optimized reaction conditions were applied successfully the acid before full gas pressure is achieved. to a range of diverse tert-alkyl esters (Scheme 3),25 thereby Subsequently, we sought to identify conditions for SN1 al- providing convenient access to structurally unique di-tert-alkyl kylation of the ex situ generated PH3 gas (Scheme 2C). Prior phosphonium salts. All products were isolated as air-stable, 16 attempts to alkylate PH3 or its synthetic equivalents have odorless solids on preparatively useful scales of up to 2.0 g. 17 18 exploited SN2 or hydrophosphination reactivity manifolds, a,b Scheme 2. Validation and Optimization of SN1 Alkylation of PH3 Gas Generated Within a Two-Chamber Reactor System a b Gas titration data are an average of 2 independent measurements and exhibit pseudo first order kinetics (Scheme 2B, inset). SN1 alkyla- tion conditions: aq. HCl (5.0 M, 10 equiv.) added to Zn3P2 (0.5 equiv.) at RT in chamber 1 to generate 1 equiv. PH3; RʹOTf (1 equiv.) add- ed to tert-amyl-OR (6 equiv.) at RT in chamber 2. Yields are of isolated, pure material; yields in parentheses determined by 31P NMR spec- troscopic analysis vs internal standard. c Using 3 equiv. tert-amyl acetate. Scheme 3. Synthesis of Di-tert-alkylphosphonium Salts via CMeEt2 and CEt3), or at a single Cβ-position (1a, 1d and 1e: a i t SN1 Alkylation of PH3 Gas CMe2Et, CMe2 Pr, CMe2 Bu), of each tert-alkyl substituent were